Scully, Sean P.

Abstract Chondrogenesis can occur during a bone repair process, which is related to several growth factors. Transforming growth factor β1, (TGF-β1,) downregulates the expression of type II collagen by chondrocytes in vitro, but injection of TGF-β1, into the periosteum in vivo increases type II collagen mRNA levels and initiates chondrogenesis.(1) We examined the effect of TGF-β1, on collagen gene expression in a bovine periosteum-derived cell culture system to evaluate its direct effect on the periosteum. Cultured cells expressed alkaline phosphatase and collagen proα1,(I) and proα1(II) mRNAs. A low level of type II collagen synthesis was demonstrated by immunoprecipitation. TGF-β1, had no effect on periosteal cell proliferation. Expression of collagen proα1(I) mRNA did not change with TGF-β1, treatment, but alkaline phosphatase mRNA showed a dose-dependent decrease. Expression of collagen proα1(II) mRNA was stimulated 2.7-fold by TGF-β1. TGF-β1, also caused a 2.6-fold increase in type II collagen synthesis by immunoprecipitation. These findings indicate that TGF-β1 is an enhancer of the expression of the chondrocyte phenotype of the periosteal cells and suggest that TGF-β1, is important in initiating and promoting cartilage formation in vivo.

Abstract Purpose: Increased levels of matrix metalloproteinase 1 (MMP-1) expression have been associated with poor outcome in chondrosarcoma. The existence of a single nucleotide polymorphism creating an Ets-binding site in the MMP-1 promoter may be one mechanism for elevated MMP-1 transcription. The aim of our study was to identify the prevalence of this single nucleotide polymorphism (SNP) in chondrosarcoma patients, to determine its correlation with disease outcome, and to discern whether it could serve as a prognostic marker in patients with chondrosarcoma. Experimental Design: Sixty-seven chondrosarcoma specimens were selected sequentially from an established tumor bank with a median duration of 47 months follow-up (range, 24 to 179 months). DNA was extracted, amplified with PCR, and sequenced to determine presence (GG) or absence of the Ets-binding site created by the SNP. Results: Eighteen (27%) samples were homozygous for the absence of the Ets site, 34 (51%) were heterozygous for the SNP, and 15 (22%) were homozygous for the SNP. The 5-year overall survival rate for patients was 78, 80, and 84%, respectively (P = 0.5527). The disease-free survival rate was 16, 63, and 76%, respectively (P = 0.0801). The 5-year disease-free survival rate for patients with the homozygous G/G genotype was 16%, compared with 71% for patients who were either homozygous or heterozygous for the GG allele (P = 0.0444). Conclusions: Despite a statistical correlation between MMP-1 gene expression and outcome in chondrosarcoma, this study demonstrates an absence of a correlation between the presence of the SNP and prognosis in patients with chondrosarcoma.